Most diabetes develops in adults, and is characterized by a lengthy period during which there is a progressive loss in the ability to metabolize carbohydrate ("glucose intolerance") ultimately culminating in fasting hyperglycemia. The ability to use glucose depends upon an adequate secretion of insulin by the B-cells of the pancreas and ability of the secreted insulin to inhibit endogenous production of glucose and acceleration of glucose use by cells. To understand the events in the development of diabetes, it is important to be able to measure, accurately and easily, those factors which contribute to glucose tolerance: insulin sensitivity, B-cell responsiveness and "glucose effectiveness" the ability of glucose to enhance its own metabolism. The present proposal continues studies directed at the use of simple ("minimal") mathematical models, implemented on the computer, to quantify factors determining glucose tolerance. These models depend upon the data generated following glucose and tolbutamide injection. The accuracy of insulin sensitivity measurements in normal subjects has been shown; in the present studies we turn to the assessment of insulin sensitivity in hyperglycemia (i.e., in diabetic animal models), because such assessment is necessary for studies of the alleviation of the disease. Central to the model is the importance of insulin at a locus remote from the plasma which is hypothesized to be in the interstitial space; to be examined are the kinetics of movement of insulin into this "remote" compartment and its relationship to action of insulin on glucose handling. An important question is whether these kinetics are important in insulin resistance. Additionally, measurement of insulin and C- peptide will be used to derive a more accurate model of B-cell function than is now available. Development of this model depends upon new methods developed for calculating B-cell secretion directly into the portal vein, and for calculating hepatic insulin extraction. Finally, the modeling approach will be used to examine, in vivo, the relationship between insulin secretion and action, to determine in quantitative terms how these metabolic parameters interrelate to optimize the ability of the organism to dispose of administered carbohydrate. Clearly, it is this quantitative relationship between insulin secretion and insulin action which is defective in the glucose intolerant state which may precede full-blown diabetes mellitus.